1) used in IMGN901 provides for an immunoconjugate that is stable during its circulation in plasma. anti-myeloma brokers. Key words:cancer, myeloma, antibody, immunoconjugate, CD56, CD138, maytansinoid, IMGN901, BT062 == Introduction == Multiple myeloma (MM) is usually a neoplasm of plasma cells and is the second most common hematologic malignancy in the US, with an estimated 20,000 new cases diagnosed and over 10,000 deaths due to the disease each year.1The introduction of autologous stem cell transplant and new therapeutics such as thalidomide, bortezomib and lenalidomide over the last two decades has contributed to marked gains in overall survival for MM patients.24Despite these advances, MM remains an incurable disease, and emphasis has been focused on the development of additional novel agents. These brokers include not only second generation immunomodulatory brokers and proteosome inhibitors, but also compounds with alternate mechanisms of action such as histone deacetylase inhibitors, heat shock protein inhibitors and inhibitors of the Akt pathway.5 Considerable interest has also focused on the development of antibody-based therapeutics for MM. The success of antibody-based treatments in other hematologic diseases, such as rituximab in B-cell lymphoma, has provided hope that antibody-based treatments may contribute to improved outcomes in MM well. Monoclonal antibodies targeting cell surface antigens found on MM cells such as CD74,6CD38,7CD40,8IGFR9and FGFR3,10are moving toward or are in clinical development based on encouraging results from preclinical studies. Along with efforts to develop functional antibodies that could provide benefit to MM patients, substantial efforts are underway to develop therapies using antibodies conjugated to potent cytotoxic brokers. A variety of highly cytotoxic compounds are being evaluated for antibody-based delivery, including calicheamicin, doxorubicin, taxanes, maytansinoids, dolastatins and CC-1065 analogs.11,12The first of these immunoconjugates to be approved by the FDA, gemtuzumab ozogamicin, is a calicheamicin conjugate targeting CD33 in acute myeloid leukemia.13,14 We have developed a family of ELN484228 antibody-maytansinoid conjugates, designed to improve the therapeutic window of potent cytotoxic maytansinoids by targeting these microtubule-disrupting brokers to tumor cells, while limiting the exposure of normal tissues and thereby reducing side effects.11,15The conjugates comprised anti-tumor targeting antibodies coupled to cytotoxic maytansinoids through optimized linker molecules (Fig. 1). Upon binding to a target tumor cell, the antibody-maytansinoid conjugate is usually internalized by natural processes, where the conjugate is usually metabolized and active maytansinoid metabolites are released.16Several antibody-maytansinoid conjugates are in clinical evaluation, and the most advanced of these, trastuzumab-DM1 (T-DM1), is currently in phase III testing for the treatment of Her2-positive metastatic breast cancer.17 == Determine 1. == Schematic representation of antibody-maytansinoid conjugates, IiMGN901 and BT062. == IMGN901 == Immunoconjugate IMGN901 (BB-10901; huN901-DM1) is ELN484228 composed of a humanized monoclonal antibody that binds with ELN484228 high affinity to CD56 conjugated with the cytotoxic maytansinoid DM1 through a disulfide linkage. The expression of the CD56 antigen, which was identified as a neural cell adhesion molecule,18has been noted on a variety of cancer cells including small cell lung carcinoma, neuroblastoma and other neuroendocrine malignancies,19,20as well as ovarian cancers.21Within the hematopoietic compartment, while CD56 expression is normally restricted to NK cells and a subset of T lymphocytes19,22and is absent from normal plasma cells,23it is strongly expressed on MM cells in a majority of MM patients.2427Tassone et al.24demonstrated the activity of IMGN901 against CD56+MM cells both in vitro and in vivo. Target-dependent cytotoxicity was shown in co-cultures of CD56+and CD56cells. Importantly, adhesion of CD56+MM cell lines and patient MM cells to bone marrow stromal cells (BMSCs), which is known to protect MM cells from drug-induced cytotoxicity, did not protect against the specific cytotoxicity of IMGN901. Treatment with IMGN901 in a human MM tumor xenograft model in immune-compromised mice showed that this immunoconjugate was effective in both a minimal and bulky disease setting, whereas the unmodified huN901 antibody and a non-binding control conjugate were not active in the MM model. The clinical evaluation of IMGN901 was initiated with a Phase 1 study in patients with relapsed or relapsed/refractory MM who failed at least one prior therapy, and have CD56+MM (clinicaltrials.govidentifierNCT00346255). Eligible patients receive an intravenous infusion of IMGN901 on two consecutive weeks every three weeks. Objectives for the study include determination of the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs) and pharmacokinetics of increasing doses of IMGN901. Preliminary results were reported most recently at the American Society of Hematology meeting in December 2008.28Nineteen patients had received IMGN901 at the time of data cutoff ranging in dose level from 40 to 140 mg/m2. One patient experienced a DLT (grade 3 fatigue) at the 140 mg/m2dose level, Rabbit polyclonal to Receptor Estrogen alpha.ER-alpha is a nuclear hormone receptor and transcription factor.Regulates gene expression and affects cellular proliferation and differentiation in target tissues.Two splice-variant isoforms have been described. with no patients having clinically significant myelosuppression or hypersensitivity reactions. In addition, no immune response to the immunoconjugate has been detected. Maximal plasma concentrations of IMGN901 generally increased with.
